(1) Field of the Invention
This invention relates to novel intermediate compounds which are useful for synthesizing 16-phenoxy- and 16-substituted phenoxy-9-keto-prostatrienoic acid derivatives. These prostatrienoic acid derivatives are the subject matter of U.S. Pat. No. 4,178,457. Because the 16-phenoxy- and 16-substituted phenoxy-9-keto-prostatrienoic acid derivatives possess antisecretory activity, they are useful as inhibitors of gastric acid secretion in mammals.
(2) Description of the Related Art
Muchowski, U.S. Pat. No. 3,985,791, describes the invention of 16-phenoxy- and 16-(o, m, or p)-substituted phenoxy derivatives of 9.alpha.,11.alpha.,15-trihydroxy-17,18,19,20-tetranorprosta-4,5,13-trans-t rienoic acids and a multistep process for the production of these compounds. Because the compounds described by Muchowski contained a hydroxyl group at the C-9 and C-11 positions they are classified as belonging to the PGF series.
Van Horn, U.S. Pat. No. 4,178,457, describes the invention of (dl)-16-phenoxy- and 16-substituted phenoxy-9-keto-prostatrienoic acid derivatives and the process for producing them. Van Horn's compounds are merely the 9-keto analogues of the compounds of the Muchowski invention. Van Horn's process is a 3-step process consisting of protecting the 11.alpha. and 15 hydroxyl groups of the Muchowski compounds, whereupon Van Horn was able to selectively oxidize the 9-hydroxyl group to a 9-keto group. Thereafter, he removed the protecting groups to produce the compounds of the invention. By converting the 9-hydroxyl group of the Muchowski compounds to a 9-keto group, Van Horn converted the prostaglandin derivatives from the series designated as PGF to the series designated as PGE.
Syntex, European Patent Publication No. 0146935, describes the multistep process for making 16-phenoxy- and 16-substituted phenoxy-prostatrienoic acid esters. At page 2, line 5, Syntex identifies, as twin problems in the process of producing the aforementioned compounds, the problems of how to prepare an individual stereoisomer of the subject compounds while allowing an initial selective deprotection of the C-9 hydroxyl group so that it can be oxidized to the 9-keto functionality without also oxidizing the C-11 and C-15 groups and yet allowing the subsequent deprotection of C-11 and C-15 without degrading the resulting molecule.
Syntex's approach to the problem of selective deprotection of the C-9 hydroxyl group is to employ a base labile ether forming group such as trialkylsilyl at the C-9 hydroxyl, and a base-stable acid-labile ether forming group such as tetrahydropyranyl at the C-11 and C-15 hydroxyls.
The present invention differs from the Syntex invention in that the present invention precludes the need to selectively oxidize the C-9 hydroxyl group late in the process. Specifically, the present invention builds upon 2-(2-propynyl)-4-(triethylsilyloxy)-2-cyclopenten-1-one (U.S. Pat. No. 4,529,812), a compound which already possesses the keto group at the C-9 position and which retains the keto group on the cyclopentyl ring in enol form, thereby avoiding the steps of selective protection, deprotection, and oxidation of the C-9 hydroxyl group described by Syntex.
Moreover, the present invention differs from the Syntex invention because it precludes the need for chain extension chemistry. Specifically, the present invention precludes the need for steps 9-13 on pages 12 and 13 of European Patent Publication No. 0146935 (Syntex).
Overall, the present invention provides a more efficient route to producing 16-phenoxy- and 16-substituted phenoxy-9-keto-prostatrienoic acid derivatives than has previously been described.